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Sodium Thiosulfate for Treatment of Calcinosis Associated With Juvenile and Adult Dermatomyositis

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ClinicalTrials.gov Identifier: NCT03267277
Recruitment Status : Recruiting
First Posted : August 30, 2017
Last Update Posted : March 29, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Environmental Health Sciences (NIEHS) )

Brief Summary:

Background:

Dermatomyositis (DM) and juvenile dermatomyositis (JDM) cause inflammation in the muscles. People with DM and JDM can develop calcium deposits in places they should not, known as calcinosis. Calcinosis can be painful and cause disabilities and other problems. Researchers want to learn more about calcinosis to find treatments for it.

Objective:

To test if sodium thiosulfate (STS) can treat people with DM with calcinosis.

Eligibility:

People ages 7 and older who have moderate or severe calcinosis. They must have stable DM and calcium deposits in the torso or at least 2 limbs.

Design:

Participants will be screened with:

  • Medical history
  • Physical exam
  • Muscle strength and function tests
  • Blood and urine tests

Participants will have several visits:

  • 7-day pre-treatment visit about 10 weeks before starting STS
  • Treatment visits over 10 weeks. They will get STS 3 times a week through IV infusion. They may be hospitalized the whole time. If they tolerate the drug, they may be discharged at certain times. During these times, they will return for the infusions.
  • 3- to 5-day post-treatment visits 24 weeks and 62 weeks after starting STS.

Visits may include repeats of screening tests and:

  • Questionnaires
  • Scans: They lie in a machine that takes pictures of the body. They may be injected with a radioactive agent.
  • Durometry: A small instrument applies pressure on the skin or exposed calcinosis.
  • Measurements of blood flow in the arms and fingernail blood vessels
  • Photographs of the skin
  • Kidney ultrasound
  • Tests of kidney function
  • Calcinosis aspiration: A needle placed into areas of calcinosis removes liquid.

Condition or disease Intervention/treatment Phase
Dermatomyositis Idiopathic Inflammatory Myopathies Drug: Sodium Thiosulfate Phase 2

National Institute of Environmental Health Sciences (NIEHS) has indicated that access to an investigational treatment associated with this study is available outside the clinical trial.  

Detailed Description:

Calcinosis, a serious complication of dermatomyositis, involves deposition of calcium (carbonate apatite) in soft tissue, and can result in negative impacts on quality of life and physical function. To date, there are no known effective therapies that are approved for the treatment of dermatomyositis-associated calcinosis, and there is no consensus within the medical community on the optimum treatment strategy for this often-debilitating condition.

A few reports in the literature describe treatment successes with a variety of therapeutics; however, these data are from anecdotal reports or case series and thus provide limited scientific evidence of effectiveness. Recently published reports as well as personal observations within our group have suggested that intravenous sodium thiosulfate treatment may benefit calcinosis patients. In order to gather more robust data on the utility of this medication in the treatment of calcinosis associated with adult and juvenile dermatomyositis, we propose to evaluate its effects in the context of a prospective clinical trial.

We plan to enroll participants at a single center into a single-arm, open-label study, with the overall objective of evaluating the efficacy and safety of intravenous sodium thiosulfate use in patients with moderate to severe extensive calcinosis associated with juvenile and adult dermatomyositis.

The study will enroll a maximum of 18 participants over 4 years into the full study, but up to 250 patients may screen for study entry. Eligible patients will be age 7 or older, and will have extensive calcinosis (defined as calcinosis involving the torso or 2 extremities) and moderate to severe calcinosis (indicated by a calcinosis activity visual analogue scale score of greater than or equal to 3.5 cm out of 10 cm).

Two separate evaluations performed at the NIH prior to initiation of therapy will be used as baseline data to compare in a pairwise manner to the change in assessments following treatment with sodium thiosulfate, with all other medications remaining stable. Study treatment will be 16 g/m2 sodium thiosulfate administered 3 times weekly over a period of 10 weeks at the NIH. Subjects who complete 10 weeks of treatment or reach the primary end point by week 6 will be considered completers. Following the treatment period, all participants will return to the NIH for evaluations at weeks 24 and 62.

The primary outcome will be change in calcinosis activity visual analogue scale score from week 0 to week 10 on therapy, compared to the baseline change in calcinosis activity visual analogue scale score from week -10 to week 0 pre-treatment. Secondary measures will evaluate safety and changes in components of the Calcinosis Assessment Tool, clinical assessments of calcinosis, Mawdsley Calcinosis Questionnaire, quality of life, functional disability, muscle testing (manual and quantitative), laboratory parameters (muscle enzymes, inflammatory markers, and endothelial activation markers), gene expression, calcification pathogenesis, time to improvement, and imaging. Myositis disease activity and damage will also be assessed by validated measures.

A number of research studies will be incorporated into this clinical trial in an attempt to understand the immunologic markers associated with calcification in dermatomyositis as well as the immunologic effects of sodium thiosulfate treatment.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 250 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-label Study of Sodium Thiosulfate for Treatment of Calcinosis Associated With Juvenile and Adult Dermatomyositis
Actual Study Start Date : October 5, 2017
Estimated Primary Completion Date : May 12, 2021
Estimated Study Completion Date : June 18, 2025


Arm Intervention/treatment
Experimental: Treatment
Patient will be assessed for 10 weeks off treatment and then will receive 10 weeks of treatment. They will return at weeks 24 and 52 for safety and sustainability of efficacy assessments.
Drug: Sodium Thiosulfate
Sodium thiosulfate is a calcium chelator



Primary Outcome Measures :
  1. Change in calcinosis severity visual analogue scale score from week 0 to week 10 on therapy, compared to the baseline change in calcinosis severity visual analogue scale score from week -10 to week 0 pre treatment. [ Time Frame: Week -10, 0, 10 ]

Secondary Outcome Measures :
  1. Greater improvement in quality of life score (CHQ-PF50 for children, SF-36 for adults) from Week 0 to Week 10, compared with any change in quality of life score observed during the pre-treatment period (from Week -10 to Week 0). [ Time Frame: Week -10,0,10 ]
  2. Changes in components of quality of life over time, as measured by quality of life questionnaires (e.g., SF-36, CHQ-PF50, PROMIS, Skindex-29) [ Time Frame: Week -10,0,10 ]
  3. Changes in functional disability over time, measured by CHAQ/HAQ, CMAS/AMAT/Myositis Functional Index, and physical therapy-related assessments (e.g., range of motion, 6-minute walk, timed up and go, sit to stand, Motor Functional Measure (MFM)) [ Time Frame: Week -10,0,10 ]
  4. Change in muscle strength over time, measured by manual and quantitative muscle testing. [ Time Frame: Week -10,0,10 ]
  5. Improvement of calcinosis lesions, assessed by Calcinosis Assessment Tool, durometry measurements, photography, and imaging studies [ Time Frame: Week -10,0,10 ]
  6. Changes in gene expression, measured by RNA and protein analyses (e.g., to evaluate changes due to therapy, or differences between responders and non-responders to therapy) [ Time Frame: Week -10,0,10 ]
  7. Incidence and severity of adverse events, including laboratory abnormalities, over time [ Time Frame: Week -10 to week 52 ]
  8. Improvement in or stabilization of myositis activity and damage, as assessed by the IMACS core set measures [ Time Frame: Week -10,0,10 ]
  9. Validation of the Calcinosis Assessment Tool [ Time Frame: Week -10,0,10 ]


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Ages Eligible for Study:   7 Years to 99 Years   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

    1. At least 7 years of age
    2. Meets Bohan and Peter criteria, as modified by the International Myositis Assessment and Clinical Studies Group (IMACS), for probable or definite DM or JDM
    3. Has extensive calcinosis, defined as calcinosis involving at least 2 extremities or the torso
    4. Has moderate to severe calcinosis, defined as having a calcinosis activity visual analogue scale score of greater than or equal to 3.5 cm out of 10 cm
    5. Is willing and able to comply with the requirements of the protocol and to undergo all testing
    6. Can have IV access established to receive study infusions
    7. Myositis disease activity is stable*
    8. Medications for myositis are stable for at least 6 weeks prior to study entry
    9. Men and women of reproductive potential must agree to use a reliable form of birth control during the 62-week duration of the study
    10. Subjects or their legal guardian must sign a written informed consent

      • Stable myositis disease activity will be defined by physician global and patient/parent global VAS that are <4 cm, as well as creatine kinase (CK), lactate dehydrogenase (LDH), aldolase, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) that are less than or equal to 2X upper limit of normal (ULN).

EXCLUSION CRITERIA:

  1. Is pregnant or breastfeeding
  2. Has known allergies to sodium thiosulfate or any of its components
  3. Has severe myositis disease activity as defined by patient/parent or physician global activity visual analogue scale score >4 cm out of 10 cm
  4. Has had an escalation of immunosuppressive therapy in the 2 months prior to enrollment, including the addition of a new agent to treat the patients underlying disease or an increase in dose of an existing medication used to treat the patient s disease (other than an adjustment for weight or body surface area in children)
  5. Has a malignancy or had a malignancy within 5 years of diagnosis of their DM (except for benign skin lesions or basal cell carcinoma)
  6. Known or suspected history of alcohol or drug abuse in the 6 months prior to study enrollment
  7. Has systemic lupus erythematosus, scleroderma, or a condition other than DM that is associated with calcinosis as a complication
  8. Has had a change in medications used specifically for calcinosis in the 2 months prior to enrollment, including but not limited to alendronate, etidronate, pamidronate, probenecid, colchicine, diltiazem, thalidomide, and aluminum hydroxide
  9. Has used probenecid, diltiazem, aluminum hydroxide, or hydrochlorothiazide in the 2 months prior to enrollment
  10. Has currently or has a history of any of the following: heart failure, renal impairment (GFR less than 30 representing severe renal disease), liver disease (Child-Pugh class C), arrhythmias (that are symptomatic or are concerning for progression to symptomatic arrhythmias), or recurrent kidney stones (more than one episode of symptomatic kidney stones separated by at least 1 month), or QT prolongation, or hypocalcemia, or metabolic acidosis, or hypotension
  11. Has severe osteoporosis or has had a bone fracture within a year prior to enrollment. For adults, severe osteoporosis as defined by the World Health Organization (WHO) as bone mineral density (BMD) 2.5 standard deviations below that of a young, normal adult (T-score at or below -2.5 and one or more fractures). For individuals, less than age 18, severe osteoporosis as defined by the First Pediatric Consensus Development Conference as a Z-score below -2 and one or more fractures.
  12. Has a psychiatric illness or medical non-compliance that the study team feels will make the patient unlikely to complete the study
  13. Has dysphagia where non-oral feeding alternatives are needed.
  14. Requires supplemental oxygen therapy
  15. Has >3 episodes of cellulitis requiring IV antibiotics related to calcinosis within a year prior to enrollment or cellulitis within 1 month of enrollment
  16. Previously received or currently receiving sodium thiosulfate by any route
  17. Is on an oral prednisone dose of more than 1mg/kg/day or other oral corticosteroid equivalent.
  18. Is taking any concomitant medications that are thought to alter sodium thiosulfate s effects or pharmacokinetics. Once patients have met all other inclusion criteria and no other exclusion criteria this criteria will be checked. A PharmD will evaluate the patient's current medication list for medications with the potential for interaction with sodium thiosulfate. Methodology is as follows: He or she will perform a search in two individual validated medication interaction software programs. He or she will also perform a literature search via PubMed for case reports of interactions with sodium thiosulfate. As an additional safeguard, the PharmD will evaluate the medication list utilizing principles of pharmacology and pharmacokinetics to attempt to identify any potential interactions not yet documented in the literature.
  19. Has any health conditions that, in the opinion of the investigator, significantly increase the risk of taking sodium thiosulfate or participating in any of the study procedures
  20. Weighs less than 26 kilograms.**
  21. Has a regimen of pulse steroids or IVIG that is at an interval besides every 1, 2, or 5 weeks.
  22. Has a chronic infection that makes assessment of muscle disease difficult including, but not limited to, hepatitis, HIV, HTLV 1, and HTLV 2.

    • We will attempt to enroll patients at a weight greater than 28 kg as these patients will be able to obtain all lab work for the study. Patients weighing 26 to 28 kg will only be able to obtain some of the research blood work. Patients less than 26 kg of body weight will be unable to obtain all safety labs, so will not be able to enroll.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03267277


Contacts
Contact: Adam I Schiffenbauer, M.D. (301) 451-6270 schiffenbauera2@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)    800-411-1222 ext TTY8664111010    prpl@cc.nih.gov   
Sponsors and Collaborators
National Institute of Environmental Health Sciences (NIEHS)
Investigators
Principal Investigator: Adam I Schiffenbauer, M.D. National Institute of Environmental Health Sciences (NIEHS)

Additional Information:
Responsible Party: National Institute of Environmental Health Sciences (NIEHS)
ClinicalTrials.gov Identifier: NCT03267277     History of Changes
Other Study ID Numbers: 170161
17-E-0161
First Posted: August 30, 2017    Key Record Dates
Last Update Posted: March 29, 2018
Last Verified: January 16, 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Environmental Health Sciences (NIEHS) ):
Calcinosis
Dermatomyositis
Juvenile Dermatomyositis
Idiopathic Inflammatory Myopathies
Sodium Thiosulfate

Additional relevant MeSH terms:
Muscular Diseases
Dermatomyositis
Myositis
Calcinosis
Musculoskeletal Diseases
Neuromuscular Diseases
Nervous System Diseases
Polymyositis
Connective Tissue Diseases
Skin Diseases
Calcium Metabolism Disorders
Metabolic Diseases
Sodium thiosulfate
Antidotes
Protective Agents
Physiological Effects of Drugs
Antioxidants
Molecular Mechanisms of Pharmacological Action
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Chelating Agents
Sequestering Agents